Late Sodium Current Blockade in High-Risk ICD Patients - CCC - Lead Application

描述(由申请人提供)： 对于室性心律失常事件的高危患者，治疗选择有限。单独使用β-受体阻滞剂不能提供足够的保护，索他洛尔的效果有限，胺碘酮虽然对某些患者有效，但由于其副作用和长期使用的限制，使用频率很低。心肌缺血和心肌病与心肌细胞钠超载有关。晚期钠电流在这一过程中起着关键作用。钠超载导致心肌细胞钙超载，从而增加心肌对室性快速性心律失常的易感性，增加心肌舒张性损伤，从而增加缺血和心肌损伤的风险。 雷诺嗪是一种新药，具有抗缺血和抗心律失常的特性，独特地阻断晚期钠电流，减少细胞内钙超载，改善心室舒张期。雷诺嗪的抗缺血和抗心律失常特性可能会降低心律失常事件的可能性，并改善有室性心律失常风险的患者的临床病程。 我们提出了一项随机、双盲、安慰剂对照的临床试验，招募了1200名高危ICD患者，他们将在最佳药物治疗的基础上接受雷诺嗪或安慰剂治疗。这项研究的主要目的是确定在ICD高危患者中使用雷诺拉秦是否有助于减少达到复合性心律失常终点的患者数量，所述复合心律失常终点包括需要适当ICD电击的室性心动过速或纤颤，或者死亡(以先发生者为准)。 该提案由两个集群应用程序组成，分别涵盖试验的各个组件：临床核心领先应用程序和数据协调中心。 (摘要结束)

DESCRIPTION (provided by applicant): There are limited treatment options for patients at high risk of ventricular arrhythmic events. Beta- blockers alone do not provide enough protection, sotalol has limited effectiveness, and amiodarone although effective in some groups of patients is used infrequently due to its side effects and limitations of a long-term use. Ischemia and cardiomyopathies are associated with a sodium overload of myocardial cells. Late sodium current plays a pivotal role in this process. Sodium overload leads to calcium overload of myocardial cells with consequent increased vulnerability of myocardium to ventricular tachyarrhythmias as well as increased impairment of diastolic relaxation of myocardium thereby augmenting the risk of ischemia and myocardial damage. Ranolazine is a novel drug with anti-ischemic and anti-arrhythmic properties that uniquely blocks late sodium current, decreases intracellular calcium overload, and improves diastolic relaxation of the ventricles. The anti-ischemic and anti-arrhythmic properties of ranolazine might decrease the likelihood of arrhythmic events and improve the clinical course of patients at the risk for ventricular arrhythmias. We propose a randomized double-blind placebo-controlled clinical trial enrolling 1,200 high-risk ICD patients who will be treated with ranolazine or placebo in addition to optimal medical therapy. Primary aim of the study is to determine whether ranolazine administration in high-risk patients with ICDs contributes to a decrease in the number of patients reaching a composite arrhythmia endpoint consisting of ventricular tachycardia or fibrillation requiring appropriate ICD shocks, or death (whichever occurs first). Secondary aims of the study are: 1) to determine whether ranolazine administration will decrease the likelihood of composite primary endpoints consisting of hospitalization for cardiac causes or death, 2) to determine whether ranolazine administration will decrease the likelihood of a composite secondary endpoint consisting of CHF hospitalization or death, 3) to determine whether ranolazine therapy will decrease the number of repeated hospitalizations for cardiac causes, 4) to assess whether ranolazine administration will decrease the likelihood of repeated ICD therapies, 5) to evaluate whether ranolazine administration will decrease the likelihood of appropriate ICD shocks, 6) to determine whether ranolazine therapy will be associated with improvement in exercise capacity measured by the 6-minute walk test (6MWT) and in the quality of life measured by the Minnesota Leaving with Heart Failure Questionnaire (MLHFQ), and 7) to evaluate the safety of ranolazine therapy utilizing ICD interrogation data documenting all types of ventricular tachyarrhythmias (including torsade de pointes). This proposal consists of two clustered applications covering respective components of the trial: Clinical Core - Leading Application, and Data Coordination Center. (End of Abstract)